Marketing Authorisation Application Survey results · September 2016 –February 2017 ... 3...

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Marketing Authorisation Application Survey results

Survey to Industry, Rapporteurs and EMA Platform meeting with pharmaceutical industry - 3rd July 2017

Industry speakers: Fiona Reekie

EMA speakers: Marie-Helene Pinheiro, Thomas Castelnovo, Gaelle Andriantafika and Mia Van Petegem

Direct feedback from Applicants/CHMP Rapporteurs/EMA on the process

Enable continuous improvement of MAAs submissions, processes and guidance related to centralised procedures

Understanding the performance of the initial Marketing Authorisation application procedure

Further increase transparency in interactions between EMA and its network and industry stakeholders.

Survey Objectives

Marketing Authorisation Application Survey results 1

EMA Survey Initial MAA

Period 6 Month period covered September 2016 –February 2017

Methodology Web based survey, coordinated by EMA

Survey Drafting Group CHMP representatives consulted EFPIA Working Group and Industry Stakeholder

Associations consulted

Survey Analysis Group EMA & Industry Stakeholder Associations Working Group

Survey combined the following response formats: Dichotomous scale (Yes/No) 5-point rating scale (1 Strongly disagree; 2 disagree;

3 Neither agree nor disagree, 4 Agree; 5 Strongly agree) For the analysis : 1&2 rating=disagree; 4&5=agree; 3=neither/nor

Multiple choices and multiple responses Free text

Scope Initial Marketing Authorisation Application: Procedural & content questions covering Pre-submission to validation phase PAG PSM AA

Validation Interactions

Primary evaluation phase: Day 1 to 121 Dossier Labelling Adherence SA

clarification meetings Interactions

Opinion finalisation phase: Day 121 to 210 Responses Clarification

meeting

SAG OE Interactions

Scope, methodology, timing (1/3)


Survey methodology (1)

Target Stakeholders surveyed

50% any ongoing MAA (40 to 50 MAA) reaching either Validation, D121 or

Opinion stage

Validation Late in

clock-stop or after LoQ

responses

Opinion Innovative Generic Biosimilar

Big Pharma and SMEs

EMA INDUSTRY RAPPORTEURS

• Industry • EMA

• (Co-)Rapporteurs • Industry • EMA

• (Co-)Rapporteurs • Industry • EMA


Survey methodology (2/3)

MAA Survey – Sample analysed and completion rate (3/3) Target: capture 50% of any ongoing MAA (~ 50 MAAs) reaching either Validation, D121 or Opinion

EMA survey completed Applicants survey completed 100% 97%

EMA survey completed Applicants survey completed Rapp/Co-Rapp survey completed

100% 87% 76%/79%

EMA survey completed Applicants survey completed Rapp/Co-Rapp survey completed

100% 92% 88%/90%


Results: Excellent completion rate overall for the 3 phases across participants

Validation: 65 MAAs

Day 1-121: 45 MAAs

49 MAAs for Rapp.

Day 121-Opinion: 48 MAAs

Disclaimer: Number of procedures, products, meetings etc. presented by stakeholders may vary due to the

differences of response rates.


Stakeholders surveyed



Pre-submission meeting -validation phase

This is a joint industry presentation on behalf of the trade associations shown

INDUSTRY

5

Topics covered through 27 questions:

1. Applications details

2. Procedural advice Q&A guidance

3. Pre-submission meeting

4. Accelerated assessment

5. Validation – Impact on procedure

6. Overall feedback on the interaction with EMA during pre-submission phase

63 MAA captured

Industry completion rate: 97%


PSM to Validation survey to Industry: Results

INDUSTRY

2. Pre-submission guidance

• 97% of applicants consulted the procedural advice Q&A

• 80% easily found the information* • 79% found the information clear* • For 77% information addressed the

needs* * Excludes 2 applicants who did not provide ratings

EMA Q&A guidance is a valuable aid to submission preparation


3. Pre-submission Meeting (1/3)


70% of applicants had a pre-submission meeting

Vast majority of respondents (90%, 4+5) considered the advice on their questions was clear

68% of applicants had separate pre-submission meeting with (co-) rapporteur

100% with rapporteur

86% with co-rapporteur

23% with PRAC rapporteur

7% had other contact

33% of applicants had further advice from EMA (not SA) * In 1 procedure there was no co-rapporteur

• EMA pre-submission advice is highly appreciated and considered useful

• Most frequently mentioned additional aspects to be covered are:

• Sharing of recent EMA experience on common validation issues

• Discussion of the eAF submitted by the applicant



Most valuable aspects of pre-submission meetings with members of the assessment team include:

• Possibility to introduce product, development strategy and dossier

• Face to face interaction with assessors appreciated

• Interaction with assessment team allows to:

– Exchange points of focus during dossier review and potential issues

– Address specific questions on clinical package, address potential gaps in submission package and already discuss intent to provide updated information at day 121

– Get better knowledge of (co-)rapporteur expectations

3. Pre-submission Meeting (3/3) - Feedback from (Co-)Rapporteur


4. Accelerated Assessment

From 14/63 (22%) requesting accelerated assessment:

• The majority found that guidance and reasons for acceptance/rejection were clear

• However, 14% (n=2) did not agree that guidance was clear:

• ‘Clearer guidance on user testing

requirements under accelerated assessment procedure.’

• ’We found the template for the accelerated assessment request difficult to complete.’


• 37 applicants (59%) submitted the application on the date indicated with the letter of intent.

• 17 of the 26 who did not submit on the predicted date (65%) informed EMA and rapporteurs about the potential delay.

• The gateway is working well in the majority of cases with 83% of responders reporting no difficulties that delayed submission, however, this leaves 17% reporting delays due to the gateway

5. Validation (1/2) - Submission timing and gateway


The majority of validation comments (89%) were related to amendments needed for documents.

Missing documents were at the basis of 48% of validation comments.

• These deficiencies were not necessarily flagged at the pre-submission meeting.

• In only 5% of the applications, did they delay the procedure start

• Questions regarding validation were dealt with satisfactorily in 96% of 53 cases where question was deemed applicable.

5. Validation (2/2) - Dossier content


6. Interaction with EMA contacts

The guidance on who to contact at EMA is generally clear (90% agree)

• Most applicants are satisfied with the quality (92%) and timeliness (87%) of the interaction

• In a minority of cases, experience is less satisfactory (2% and 3% give a score of 2 to quality and timeliness respectively)


Industry conclusions pre-submission - validation phase

• Overall, responses indicate that the pre-submission to validation phase does not cause major difficulties

• Pre-submission Q&A’s received good ratings but written comments indicate that improvement is possible in terms of clarity, access to the right information and level of detail.

• The opportunity to meet with EMA, (co-)rapporteur or other members of the assessment team is frequently used and highly valued

• 40% of Marketing Applications were not made on the date given in the Letter of Intent and the EMA was not consistently informed of changes in date

• Although the pre-submission meeting generally is highly graded, it does not pick up all validation issues which included missing documents in almost half of submissions

• The Submission gateway is working well in the majority of cases but 17% encountered issues Marketing Authorisation Application Survey results 15

• PSMs beneficial • Validation issues – too frequent and creating administrative burden for both

Industry and EMA

Possible solutions

– Attendance by the EMA validation team at the PSM or better communication to validation team; some agreements that are made at the pre-submission are raised during validation

– A more direct focus on validation and more structured discussion of the draft application form is proposed as a fixed item on the pre-submission meeting agenda

– Better awareness of the pre-authorisation Q&A (4.3) which lists the most common validation issues

– Applicants to request clarifications prior submission

Overall recommendations - PSM to validation






EMA

Pre-submission meeting -validation phase

EMA

17

Pre-submission to validation survey to EMA - Results



2. Validation – Impact on procedure

3. Pre-Authorisation guidance

4. Pre-submission meeting

5. Accelerated assessment

6. Overall feedback on the interaction with applicants during pre-submission phase

65 MAA captured

EMA completion rate: 100%


EMA


New Active substance: NAS, Known Active substance: KAS, Well-Established Used: WEU, Fixed Dose Combination: FDC, Informed Consent: IC,

19

33

3

9

2 3 3 4 8

51%

5% 14% 3% 5% 5% 6% 12%

MAA legal basis covered (N=65) Orphan

29% (19)

Non Orphan

71% (46)

(Non-) Orphan Medicinal Products rate

SME 26% (17)

Non SME

74% (48)

(Non-)SME rate

1. Applications details (1/2)

Orphan products & SME applicants: in line with EMA records of previous years

Sample surveyed captured significant numbers of orphan and SME

Majority of NAS legal bases (51%), followed by Generics (14%) and Biosimilars (12%) in line with current trends

Overall, sample captured can be considered representative


2015 (full year) 2016 (full year) Survey (6 months)

Orphan 23 19 19

SME 14 31 17

1. Applications details (2/2)


A short majority agreed that the dossier was complete & presented in a satisfactory way; non negligible proportion of “neither agree or disagree” rating

2. Validation: impact on the procedure (1/3)

21

AGREE 38%

AGREE 51%

37%

37%

25% 12%

0%10%20%30%40%50%60%70%80%90%

100%

Dossier complete /justifications present

(N=65)

Dossier satisfactory /justification easy to find

(N=65)

Disagree

Neither agree nordisagree

Agree

22

Validation comment in almost all cases (97%) – Only 2 applications with no question. Vast majority of applicants respond accordingly to the agreed timelines (94%)

In half of the applications (44%) the responses were incomplete and required a follow up

Issues most commonly seen are purely administrative & non blocking issues Quality + GMP aspects (92%): most frequent issues relate to inconsistencies of the Application Form

(90%) with qualitative and quantitative composition of the medicinal product (62%)

(Non) clinical/GLP/GCP issues (83%): more than half of the issues relates to GLP/GCP information, as much as observed for issues related to Module 5

Product Information (30%):95% relate to inconsistencies with the application form (ATC, strength, pharmaceutical form, route of administration, container, pack size, product name)

Validations issues almost systematically on the application form Most queries related to quality & GMP matter (81%)

Applicant’s contact person & details & (75%)

Nonclinical/clinical and GCP/GLP aspects (65%)




EMA should investigate opportunities to increase awareness on:

the validation process

the most common issues encountered at validation (published on EMA website)

the procedural pre-submission guidance

Applicant should also increase awareness on the EMA requirements; particular focus could be on reducing discrepancies in the application form and the dossier submitted

Applicants are encouraged to request clarifications prior submission



Short majority (57%) agreed that applicants

were aware of the procedural guidance (Q&A on

EMA website)

Non negligible proportion of “neither agree nor

disagree” rating

Analysis per legal basis and SME vs non SME did

not show a clear pattern

Combined with the almost 100% validation

questions rate, these results indicate the need for EMA to increase general awareness and ease access to the procedural presubmission guidance

24

AGREE 57%

32%

11%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Applicant aware of the procedural guidanceQ&A on the EMA website to prepare MAA

submission (N=65)

Disagree


Agree

3. Pre-authorisation Guidance

Pre-submission dialogue in almost 85% applications surveyed

Pre-submission meeting in almost 75% (48/65) of the submitted dossier

Almost 10% of interactions through written/verbal advices (when no meeting took place)

Approximately 15% of applications with no interaction prior submission with EMA (mainly Generics and informed consent)

A follow-up advice necessary in more than 50% of the PSM

Most of SME (14/17) and orphan applications (17/19) had a PSM

PSM with EMA was requested for all biosimilar applications



More than 92% of the PSM topics with EMA relates to (Non)Clinical + Clinical, GLP/GCP information followed by the PI aspects: - (Non)Clinical+GLP/GCP:92%

- Product Information: 77%

- Regulatory/Procedural:75%

- Quality+GMP: 67%

- Administrative: 65%

- Pharmacovigilance: 52%

- Transparency:23%

- Other: 19%

(Non) Clinical + Clinical, GLP/GCP topics (N=44)

Product Information topics (N=37)

Various topics are discussed but mainly related to the development programme and the SmPC for the PI

4. Pre-submission Meeting – Topics (2/4)


SAMPLE COMMENTS

Most valuable aspects gathered: Advice provided on regulatory requirements e.g. legal basis and its requirements, orphan similarity/maintenance, accelerated assessment, GMP, RMP. Face to face meeting with the applicant Clarification on the procedure Presentation of the product and the development programme

Short majority agreed that the meeting helped identified validation issue & assessment issue; non negligible proportion of “neither agree or disagree” & “Disagree” rating

AGREE 56%

AGREE 52%

31% 33%

13% 15%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Meeting helped identifyvalidation issue (N=48)

Meeting helped identifyassessment issues (N=48)

Disagree


Agree

4. Pre-submission Meeting – Usefulness (3/4)



Overall, there is a very high level of interaction with EMA prior to submission, mostly via pre-submission meetings

Meetings helped identified validation issues as no blocking validation questions raised; however ~100% non-blocking validation issues

Investigate opportunities to make better use of pre-submission meeting to further anticipate and identify the non-blocking validation issues (right forum?)

Over 65 applications, 22% [14] requested an accelerated assessment

All justifications for requesting AA were in line with available template, 13 were discussed at PSM meeting and were timely received

Very good level of awareness from applicants on the AA process & early dialogue occurred


5. Accelerated Assessment

Overall EMA feedback positive

Overall interaction during pre-submission activities could be improved

EMA satisfied with the quality of the information & timeliness of interactions during the pre-submission phase

AGREE 65%

AGREE 62%

29% 29%

6% 9%

0%10%20%30%40%50%60%70%80%90%

100%

Satisfied with the quality ofthe information (N=65)

Satisfied with the timelinessof the interaction (N=65)

Disagree

Neither agree nordisagreeAgree

6. Satisfaction on interaction with applicants





Primary evaluation phase: DAY 1-121

INDUSTRY Survey methodology (1)



30

Day 1 to 121 survey to Industry - Results



2. Assessment reports in primary phase

3. Labelling review in primary phase

4. Clarification meeting

5. Overall feedback on the interaction with EMA during the primary assessment phase

39 MAA captured



INDUSTRY

Majority of Assessment Reports received within 2 days of the due date

54% of Day 80 Rapp Assessment Reports

67% of Day 80 CoRapp Assessment Reports

79% of Day 94 PRAC Rapp Assessment Reports

30% of respondents were proactively informed of a delay

2. Assessment phase: AR circulation timeliness


Clarity of assessment reports was reported as a positive in the majority of cases

2. Assessment phase: AR Clarity


The majority of respondents received a single file encompassing comments from both the CHMP and EMA

2. Assessment phase: product information circulation


The clarity of comments on Product Information was considered positive by the majority of respondents

3. Assessment phase: product information clarity


Clarification meetings more common for NCE MAAs

4. Clarification meetings (1/2)


Clarification meetings are well regarded



Contact with the EMA was

generally positive

4. Interaction during primary phase


Conclusion

• Overall, responses indicate that Day 0 to Day 120 of the Centralised Procedure is well run

• Although assessment reports are usually provided in accordance with the timetable, delays are not uncommon and are not always proactively communicated to the Applicant

• The Assessment reports, questions and major objections are of high quality (clarity, consistency etc) as are the comments on the Prescribing information and mock ups

• The clarification meetings are particularly valued for their usefulness, especially for discussing the Applicant’s response strategy

• Interactions with EMA are very positive


Investigation into the delay of the (Co-)Rapp Assessment Reports may be warranted

• Is sufficient time included for EMA legal review or is this a resource issue for the Rapporteurs?

• Should this be reflected in the published procedure timetables?

• Consistency of communication from EMA to Applicant regarding delays would be appreciated

EMA Contact Points

• Although 82% of responders thought the guidance clear on who to contact at the EMA, the comments referred to some uncertainty regarding contacting EPL/EPM

40

Overall recommendations



EMA EMA

Primary evaluation phase:

DAY 1-121




41

Day 1 to 121 survey to EMA - Results



2. Labelling review in the primary assessment phase


4. Overall feedback on the interaction with applicants during the primary assessment phase

45 MAA captured



EMA


Orphan 24% (11)

Non Orphan

76% (34)

Proportion of Orphan Medicinal Products

SME 27% (12)

Non SME 73% (33)

Proportion of SME

30

3 7

1 0 0 0 4

67%

7% 16% 2% 0% 0% 0% 9%

8(3) NAS 8(3) KAS 10(1)Generic

10a WEU 10b FDC 10c IC 10(3)Hybrid

10(4)Biosimilar

MAA legal basis covered (N=45)


43

1. Application details


EMA mainly neither agrees nor disagrees (rated 3)

• Most relevant comments: “almost empty SmPC”; principle of SmPC guideline not always correctly implemented; poor compliance with the QRD template & SmPC guideline”

Adherence to guidance & template could be improved

EMA should investigate opportunities to increase awareness on existing guidances

44

AGREE 38%

49%

13%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

PI presented in a satisfactory way &followed the relevant guidances [QRD,

SmPC] (N=45)

Disagree


Agree

2. Labelling review

SAMPLE COMMENTS

“Written clarification substituted meeting in 2 occasions;

Very positive feedback on the usefulness of the meeting;

Meeting clearly needed & much facilitated the understanding of major issues.”

Meeting in 62% [28] of applications (<2/3 applications)

• Applicants clearly specified scope & topics to be discussed – 93%

• Briefing document a week before the meeting – 79%

Most of the meeting happened for NAS (85%); and/or orphan product (82%) and/or SME applicants (83%)

EMA considered that the meeting facilitated the progress of the procedure in almost ¾ of the meetings

Majority of applicants displayed very good adherence to the

guidance with the requirements (clarity of scope & topics and briefing documents provided timely)

(across 45 applications) 3. Clarification meetings


SAMPLE COMMENTS

“Applicant communicated well, in a timely and pro-active manner; No problems identified with the interaction with the applicant at all.”

Overall EMA feedback positive

EMA satisfied with the quality of the information (69%) & timeliness of interactions (73%) during the 1st phase of assessment

AGREE 69%

AGREE 73%

16% 22%

15% 5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%



Disagree


Agree



Survey methodology (1) Stakeholders surveyed



(Co-)RAPPORTEURS

Primary evaluation phase: DAY 1-121

47

Day 1 to 121 survey to Rapporteurs- Results



2. Satisfaction with relevant parts of the dossier (Quality, Non-clinical, Clinical, Product Information, RMP)

3. Adherence to scientific advice

4. Labelling review in primary phase


6. Overall feedback on the interaction with applicants during the primary assessment phase

49 MAA captured

Completion rate: 76/79% (Rapporteur/Co-Rapporteur)


RAPPORTEURS

2 & 4. Dossier content satisfaction level Positive ratings varied from 32% to 65% of responses (lowest: Clinical Overview and PI well substantiated in

overview) Large proportion “undecided/3” ratings

20 17 23 19 18 13

21 20 19 15 16

8

11 8 5 8

10 12

8 8

9 11 12 15

3 4 7 2

8 5 4 1

7 4 7 2

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp

Quality Overallsummary

Non clinicaloverview

Clinical Overview Non-clinicalSummaries

Clinical Summaries PI wellsubstantiated in

overview

Disagree

Neitheragree/disagreeAgree


17 17 19 13 17 14

7 7 9 10 9 8

7 7 9 8 11 9

0%10%20%30%40%50%60%70%80%90%

100%

Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp

Easy locatinginformation

Dossier mature High quality overallcontent

Disagree

Neither agree/disagree

Agree

Average level of satisfaction of initial MAAs content [45-55%]

Considerations: in 20-25% responses rapporteurs considered dossier not mature enough and information not easy to find. In 30% responses rapporteurs were not satisfied with the quality of the overall content.

2. Dossier overall content quality


3. Adherence & scope of scientific advice

18.85%

14.75%

15.57% 27.05%

19.67%

4.10%

QualityNon clinicalClinical PK/PDClinical EfficacyClinical Safety/RMPOther

6

4

7

4 4 6 10

8

9

9

2

5

1

3 2

5

3 6

2

5

2 2 1 1 1

0

4 3

0 0

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp

Quality Non clinical Clinical PK/PD Clinical efficacy Clinical safety/ RMP

Agree Neither agree/disagree DisagreeMarketing Authorisation Application Survey results 51

Adherence to Scientific Advice in the majority of the cases

Examples of non-adherence :

• Quality : Process validation package; definition of starting materials; amount of stability data

• Clinical : disease model; choice of comparator; choice of endpoint

If deviating justification to be presented in Overview

3. Adherence to scientific advice: scope details


Overall feedback Day 1-121

Overall ± 60% satisfaction with information on response date change and response to ad-hoc clarification requests

6. Interaction with applicants


Conclusions and recommendations Responses indicate moderate level of satisfaction with the content of the initial dossier (40-50% positive ratings on

overall content, 30% negative) Improvements could be made in the presentation of the application, e.g. clinical overview including

substantiating the information proposed for the PI.

Applicants are encouraged to ensure all relevant data can be easily located and include clear references to the location of relevant data/information in CTD (hyperlinks).

The need for mature dossiers was highlighted.

Most applications considered adherent to Scientific Advice

In the event of deviation(s), a clear and sound justification is recommended in the MAA; this is likely to facilitate the proceeding of the assessment

Feedback on interaction with applicants generally positive

Applicants should provide accurate estimates of the planned submission dates – be as realistic as possible. This is important for the work schedules of the assessment teams.

In case of changes to submission deadlines, EMA and Rapporteur teams should be informed asap.






Opinion finalisation phase:

Day 121-210

INDUSTRY

55



2. Assessment reports in final assessment phase


4. SAGs/Ad-hoc experts groups

5. Oral explanation at committee plenaries

6. Finalisation of commitments and opinion documents

7. Overall feedback on interactions with applicants during the final assessment phase

44/48 MAA captured



Day 121 to CHMP Opinion survey to Industry: Results

INDUSTRY

Majority of Assessment Reports

received within 2 days of the due date

51% of Day 150 Rapp Assessment Reports (n=37)

68% of Day 194 Rapp Assessment Reports (n=31)

30% of respondents were proactively informed of a delay

2. Assessment phase: AR circulation timeliness


Comments and questions were

clear and substantiated in

assessment reports

2. Assessment phase: LoQ clarity


In most cases, a single consolidated assessment report

was received at D180

2. Assessment phase: 180 AR circulation timeliness


Clarification meetings were

held for: 9 ‘Other’ licences

5 NCEs 2 Biosimilars



Clarification meetings are

particularly useful for discussing

response strategy

3. Clarification meetings usefulness (2/3)


Clarification meetings are well

regarded

3. Clarification meetings usefulness (3/3)


Only 2 SAGs and 3 Oral explanations were held - too few for any conclusions

4 & 5. SAGs and oral explanation


Changes in type of MA can occur

during assessment

6. Opinion category switch


65

More conditions on the licences are imposed during assessment

than are foreseen by the Applicant

6. Opinion category


66

There are high levels of satisfaction with

EMA interaction during finalisation stages to

CHMP Opinion

6. Interaction level of satisfaction


CHMP Opinion was not received within 2 working

days in a number of cases

6. Opinion receipt timeliness


Contact with the EMA was generally

positive

7. Interaction with EMA


Conclusion (1/2)

• Overall, responses indicate that Day 121 to Day 210 of the Centralised Procedure is well run.

• Delays in assessment reports are similar to those seen earlier in the procedure and again, are not always proactively communicated to the Applicant

• The Assessment reports, questions and major objections are of high quality (clarity, consistency etc)

• As for D0 – D120, the clarification meetings are particularly valued for their usefulness, especially for discussing the Applicant’s response strategy, too few SAGs and Oral Explanations were held to draw any conclusions


Conclusion (2/2)

• Standard licences were granted in the majority of cases, however, a few applications for standard licences were granted Conditional approval/approval under Exceptional Circumstances

• More conditions (ANX, Specific Obligations, RMP studies) were imposed during assessment than had been proposed in initial applications

• Interactions with EMA and their facilitation of documents for opinion are very positive

• However, the actual opinion was quite often received at least 4 days post CHMP meeting leading to concerns regarding the timelines for providing translated annexes and there was a lack of awareness regarding timing/content of the EMA CHMP meeting Press Release


Again, investigation into delay of Assessment Reports may be warranted

• Is sufficient time included for EMA legal review or is this a resource issue for the Rapps?

• Should this be reflected in the published procedure timetables?

• Consistency of communication from EMA to Applicant regarding delays would be appreciated

There was a lack of awareness of the possibility of further rounds of D180 questions

• Perhaps a Q and A in Pre-authorisation guidance, including the timetables for assessment, would be helpful

The timing of receipt of CHMP Opinion was not consistent and there was a lack of awareness of the timing/content of the Press release from the CHMP meeting

• Perhaps a Q and A in Pre-authorisation guidance would be helpful

Overall recommendations





EMA EMA

OPINION FINALISATION PHASE: DAY 121-210

72

Day 121 to 210 survey to EMA - Results




3. SAGs/Ad-hoc experts groups

4. Oral explanation at committee plenaries

5. Finalisation of commitments and opinion documents

6. Overall feedback on interactions with applicants during the final assessment phase

48 MAA captured



EMA



74

14

3

15

1 2 4 3

6 29%

6%

31%

2% 4% 8% 6% 13%

MAA legal basis covered (N=48) Orphan 17% (8)

Non Orphan

83% (40)

Proportion of Orphan Medicinal Products

SME 10% (5)

Non SME 90% (43)

Proportion of SME vs. non SME

1. Application details (1/2)

Orphan products & SME applicants: in line with EMA records of previous years

High proportion of generic and informed consent (IC) applications: almost 40% of the opinions

May explain certain results of this survey phase: low number of clarification meetings, SAGs/Ad-hoc expert groups and oral explanations.


2015 (full year) 2016 (full year) Survey (6 months)

Orphan 18 (8 in 1st 6 months) 16 (8 in 1st 6 months) 8

SME 9 5 5

1. Application details (2/2)

SAMPLE COMMENTS

“Meeting was crucial; Meeting particularly useful as allowed applicant to define their strategy and led to the cancellation of the Oral Explanation; Meeting needed to clarify complex issues and explore options for a conditional approval.”

Meeting in 42% [20] of applications (<50% applications)

• Applicants clearly specified scope & topics to be discussed – 100%

• Briefing document a week before the meeting – 80%

Approximately 50% of the meeting happened for NAS; almost all orphan had a clarification meeting; 2 SME had a meeting

EMA considered that the meeting facilitated the progress of the procedure in almost all meetings – 85%

Majority of applicants displayed excellent adherence to the

guidance very good level of awareness

High proportion of generics and informed consent may explain the low number of meetings

(across 48 applications)

2. Clarification meetings


Only 2 meetings captured in the survey

Briefing documents & applicant presentations considered informative and clear for one meeting, no opinion for the 2nd meeting

In both cases: debriefing meeting occurred as per EMA process & EMA strongly agreed that the discussion contributed to reaching the final outcome

Results showed that Applicants, Rapporteurs and EMA showed excellent process compliance

No conclusion can be drawn from the only 2 cases


3. SAGs or Ad Hoc expert group meetings

Only 3 OEs captured in the survey; OE scopes: Quality / Efficacy / Bioequivalence

Objections subject to the OE raised from D180 in 2 cases, from D120 for the quality objection.

Applicants submitted presentations in a timely fashion in all cases. A debriefing meeting after the OE occurred systematically as per EMA process; with systematic attendance from the Rapporteurs, EPL and PM. Other specialists (Regulatory, Quality, RMS) attended on an ad-hoc basis.

Results showed that Applicants, Rapporteurs and EMA showed excellent process

compliance

No conclusion can be drawn from the only 3 cases


4. Oral explanation

SAMPLE COMMENTS

“Exchange of information and documents with applicant and rapporteurs as well as finalisation was very smooth and efficient; Company was quick to implement requested changes in RMP and PI, prior to opinion; The revised RMP came late which resulted in a delay in sending out final documents.”

Significant majority of applicants provided the requested PI (79%)

and RMP (75%) revisions for opinions finalisation in a timely manner

AGREE 79%

AGREE 75%

15% 19%

6% 6%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Revised PI timely provided(N=48)

Revised RMP timely provided(N=48)

Disagree


Agree

5. Finalisation of commitments and opinion documents (1/2)


Timing for Annex II conditions


15% (7)

6% (3)

15% (7)

64% (31)

D120

D180

AfterD180

Nocondition

Annex II condition in 35% (n=17) of the opinion

Almost 60% conditions were raised from D180 only i.e. last stages of the evaluation

EMA could investigate with Committees

opportunities to prompt earlier potential need for conditions to the marketing authorisation

5. Finalisation of commitments and opinion documents (2/2)

SAMPLE COMMENTS

“Applicant was professional & pro-active; Company was fully aware of EMA processes & procedures, timelines and interactions with committees; Interaction with company was very good and with quick responses, information submitted was clear and well organised.”

Overall EMA feedback very positive (multiple positive comments)

EMA highly satisfied with the quality of the information (86%) & timeliness of interactions with applicants (84%) during the last phase of assessment

AGREE 86%

AGREE 84%

12% 10% 2% 6%

0%10%20%30%40%50%60%70%80%90%

100%



Disagree


Agree






(Co-)RAPPORTEURS

Opinion finalisation phase: Day 121-210

82

Day 121 to Opinion survey to Rapporteurs- Results



2. Satisfaction with responses (Quality, Non-clinical, Clinical, Product Information, RMP)


4. Scientific Advisory Group/Ad-hoc Expert Group

5. Oral explanation

6. Overall feedback on the interaction with applicants during the final assessment phase

48 MAA captured

Completion rate: 88/90% (Rapporteur/Co-Rapporteur)


RAPPORTEURS

Positive ratings in 60-80% suggest high level of satisfaction with the responses to LOQ/LoOIs. PI & RMP responses scored slightly lower compared to other areas.

22 19

18 13 24 21

20 17 17 12

11 4

3 4 5

3

9

8 9

6

2 2 0 0 2 1

6 1 2 0

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp Rapp Co-Rapp

Quality Questions Non-clinicalQuestions

Clinical Questions Product Information RMP

Disagree

Neitheragree/disagreeAgree

2. Applicant’s responses to LoQ/LoOI - satisfaction level


Overall, 28/70 responses confirmed that a clarification meeting was held during the second phase of the assessment.

60% agree meeting is helpful. Only ± 40% considered response strategy was well substantiated in the briefing documents

10 11 8 9

5 6

9 8

1 4

3 5

6 7

3

3

2 0

2 1

2 2 1 4

0%10%20%30%40%50%60%70%80%90%100%

Co-RappRappCo-RappRappCo-RappRappCo-RappRapp

d) Rapp feedback reflectedin responses

c) Helpfulness of Meetingb) Response Strategy wassubstantiated

a) Briefing Document wasclear

Disagree

Neitheragree/disagree

Agree

3. Clarification Meetings


Only 2 SAGs and 3 Oral Explanations covered by the survey.

Generally positive ratings for SAGs:

Informative briefing documents and presentation by applicant.

Expert discussion helpful to reach final outcome.

Mixed feedback on helpfulness of Oral Explanations.

Overall, numbers too low to draw firm conclusion.

4 & 5. SAGs and oral explanation


19 18

23 21

2 5

1 3

2 2 1 1

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Co-RappRappCo-RappRapp

b) Adequate responses by applicant toRapp requests for clarification

a) Good info on change in D181response submission date

Disagree

Neither agree/disagree

Agree

Very positive, higher satisfaction level compared to primary assessment phase

6. Overall feedback on interaction with applicant


Conclusions and recommendations

Better level of satisfaction with responses to LOQ & LoOIs (approx.

70% positive ratings)

PI & RMP responses scored slightly lower compared to other areas, but still good ratings carefully consider all CHMP comments on the PI/RMP - when deviating from CHMP requests, clearly explain reasons why.

Same recommendations as at D1-121 regarding need for information to be easy to locate and maturity of the dossier/responses.

Late submission of large datasets are problematic and should be avoided.


Clarification meetings generally considered helpful. However, some negative ratings.

The need for a clarification TC/meeting should be carefully considered.

The main purpose of the meeting is to make sure that the issues with the application are well understood and to facilitate the preparation of responses.

No pre-assessment/endorsement of responses.

If Applicants wish to have a clarification TC/meeting, a clear outline of the response strategy should be presented to make the most of the meeting.

Feedback on interaction with applicant at Opinion stage very positive. Same recommendations as for Day 1-121.


Conclusions and recommendations




General conclusions

90

General conclusions

91

Overall very good level of satisfaction across the 3 phases (increase from validation to opinion)

High level of interaction during pre-submission phase (PSM)

Good quality of information and timeliness of the interaction (especially at opinion phase)

Very good level of awareness of applicants on guidance for clarifications meeting and accelerated assessment

Clarification meeting generally considered helpful

Most applications considered adherent to scientific advices

EMA & (Co-)Rapporteurs’ positive feedback across the 3 phases of the procedure


92

EMA

Increase awareness on validation process (most common issues encountered)

Will help identification of non blocking validation issue prior submission

Increase awareness on SmPC guidance & QRD template and pre-authorisation guidance.

Assessment Reports/ final opinion - Circulation timelines and communication of delays

Optimise timing for Annex II condition request

Clarify role EPL vs PM

Areas identified for optimisation


General conclusions

93

Industry

Accuracy of MAA submission date – communications of delays to EMA & Rapporteurs

Validation: increase awareness on guidance & consistency between application form, PI and dossier

Improve the presentation of the application (data easily located, hyperlinks etc.)

Adherence to PI guidelines (SmPC & QRD) & better substantiate the proposed PI in the clinical overview and address CHMP comments

Need for mature dossier & responses – late submission of large datasets should be avoided

Areas identified for optimisation


General conclusions

Acknowledgement

Susan Bhatti (Merck KGaA, EFPIA)

Sally Bruce (GSK, EFPIA)

Nadege Leroux (Celgene, EFPIA)

Katarina Jelic Maiboe (Novonordisk, EuropaBio)

Vesna Schauer-Vukasinovic (Sandoz, Medicines for Europe)

Kevin Sinnett (Amgen, EFPIA)


Evdokia Korakianiti

Gaelle Andriantafika

Jordi Linares Garcia

Marie-Helene Pinheiro

Mia Van Petegem

Michael Berntgen

Pavel Balabanov

Stefanie Prilla

Agnes Gyurasics

Andrea Laslop

Concepcion Prieto Yerro

Daniela Melchiorri

Greg Markey

Karsten Bruins

Pierre Demolis

Tomas Salmonson

Survey responders

Industry Team CHMP sponsors EMA Team Survey developers:

Aline Caromelle, Simona Simoiu

Thomas Castelnovo

Victoria Palmi Reig

Vilma Pakenyte

Zigmar Zebris

Aliki Sydoninou

Thank you for your attention

European Medicines Agency 30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact

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